Re-emergence of scarlet fever: old players return?

KEYWORDS:

• Scarlet fever
• Streptococcus pyogenes
• outbreak
• integrative and conjugative elements
• horizontal gene transfer
• ssa
• speA
• speC

Streptococcus pyogenes (GAS) can cause a wide range of infections, such as pharyngitis, impetigo, or severe soft-tissue infections. GAS is also responsible of postinfectious immune syndromes, such as poststreptococcal glomerulonephritis, acute rheumatic fever, and can cause toxin-mediated diseases, such as toxic shock syndrome, and scarlet fever. Scarlet fever has been a feared killer in the past: epidemics were common in the eighteenth and nineteenth centuries throughout Europe, Great Britain, and US, but this childhood disease nearly disappeared during the twentieth century [1,2]. However, several countries recently face a re-emergence of scarlet fever and the reason for these new outbreaks remains unclear. It is hypothesized that this phenomenon is due to microbial determinants, such as new strains with higher virulence capacities. This could come from the acquisition by Horizontal Gene Transfer of mobile genetic elements carrying superantigenic virulence factors and antimicrobial resistance determinants, or from newly acquired mutations of virulence regulators, such as the two component covRS operon, in the M1T1 strain 5448 (although this very mutation was also shown to decrease colonization and thus probably transmissibility) [3,4]. It is likely that environmental and host-related factors are also involved. The lack of immunity of young children, due to the very restricted protection conferred by antibodies toward the M protein, with little cross-immunity toward other M types (even restricted to closely related strains within the same M-type) probably also plays a role in this re-emergence [5,6]. Finally, multiple combined factors, including meteorological variations differing, for example, between Hong Kong or mainland China (low humidity, scarce rainfall, and higher temperatures seem to favor outbreaks) and Great Britain (winter and early spring correlates with higher case number) provide an additional level of complexity [7].

During the past decade, major outbreaks have been reported in Vietnam (over 23,000 cases in 2009), mainland China (>100,000 cases reported by the Chinese Ministry of Health), Hong Kong (>1000 cases, while before 2011 only sporadic cases were reported with the last major peak of 126 cases in 1976), and in the United Kingdom [8–12]. With 17,586 cases reported in 2015 and 7799 cases reported to Public Health England in 2016, until April 8 (Health Protection Report, Volume 10 Number 14), this is the biggest outbreak in this country since 1969; at that time, there were 16,093 new cases followed by a long disease-free period [8]. Smaller outbreaks were reported in Canada (over 100 cases in 2012), Kansas, USA in 2012, Mexico in 2000, and Valencia, Spain (40 cases in 2011) [13,14]. Typing, molecular characterization, and often genome sequencing of scarlet fever GAS isolates have been performed in several cases and brought light upon the genetic determinants of GAS and scarlet fever [9,11,15].

In Great Britain, the 2016 scarlet fever circulating strains were emm-typed and appear to be mostly emm1 (39%), emm12 (13%), emm89 (9%), and emm28 (4%). Emm3 strains frequency has decreased (4%) compared to previous years. Thus, no single emm-type and probably not a single clone among emm-types seems to be the cause of this outbreak. Nevertheless, no genetic molecular study has been so far published. Hopefully, the presence of common prophage genetic elements harboring virulence or resistance determinants across several emm types should be revealed in the future. Interestingly the novel circulating emm89 clade is not a predominant scarlet fever producing strain, although a majority of isolates carry speC [16].

In contrast, the Hong Kong and mainland China outbreak from 2011 was mainly caused by tetracycline and macrolide resistant Streptococcus pyogenes emm12. Interestingly, this large outbreak with thousands of children – many with severe illnesses – is probably the most studied scarlet fever outbreak in the sequencing era. Tse and colleagues established, after a phylogenetic analysis (PFGE) of 22 GAS emm12 scarlet fever isolates, that this outbreak was not clonal but rather polyclonal [11]. Interestingly, sequencing of certain isolates identified two horizontally acquired elements: an integrative and conjugative element ICE-emm12 providing tetracycline (tetR) and macrolide resistance (ermB), and prophage ΦHKU.vir encoding the superantigens ssa and speC together with the DNase Spd1 virulence factor.

It is well known that GAS genome plasticity is mainly due to the presence of horizontally acquired genetic elements that harbor virulence factors and/or resistance genes [17]. No covRS two-component system mutation was found in the sequenced isolates; this is not surprising since several authors suggest covRS to be related to invasive GAS infections, such as necrotizing fasciitis rather than pharyngitis [4,11,15]. These mobile genetic elements represented more than 80% of scarlet fever isolates associated with the outbreak. Thus, although this outbreak was polyclonal, its unifying characteristic seemed to be the presence of common horizontally acquired elements (ICE-emm12 and ΦHKU.vir), carrying antibiotic resistance genes and virulence factors (including ssa). Of great interest, a recent report shows that 25 out of 34 emm1-type (M1T1-related clone), which was the second most prevalent type of the Hong Kong epidemic and was a frequently isolated emm-type in the mainland China outbreak, also carries an ICE-12-like element, and a ΦHKU.vir-like element (ΦHKU488.vir) [9]. This suggests that these are not a clonal-related, or an emm-type-related outbreaks, but instead mobile genetic elements-driven outbreaks.

Some GAS emm-types (or M type) are known to be rheumatogenic or nephritogenic. Although previous studies suggest that particular M-types can induce scarlet fever, not every study supports this concept. Surprisingly, the physiopathological mechanism of this disease is still not clear. As such, scarlet fever is considered a toxin-mediated disease, but the toxin (or toxins) causing scarlet fever remains insufficiently established. Pyrogenic toxins SpeA and/or SpeC are believed to be responsible for this syndrome; nevertheless, a strict association between scarlet fever and these exotoxins is not always detected [18]. This contrasts with other toxin-mediated diseases, where the toxin that triggers the disease is well established, such as in Staphylococcus aureus-related toxic shock with Toxic Shock Syndrome Toxin 1 or enterotoxins related to food-borne diseases. In GAS, several toxins, or toxin combinations seem to be able to trigger scarlet fever. In a study by Costa and colleagues, 101 scarlet fever GAS isolates from Portugal were emm-typed, PFGE and toxin profiled and compared with 202 non-scarlet-fever pharyngitis isolates, in a non-epidemic context [19]. One PFGE-based cluster, containing mostly emm87 isolates was, after analysis, more frequently associated with the disease. In contrast, among superantigens (speF, speG, speH, speJ, speK, ssa, smeZ, speA, speB, speC, speI, speL, and speM), only speA, speC, and ssa, either alone or in combination, were associated with scarlet fever, the speC-ssa combination showing the strongest association [19]. Mobile genetic elements’ composition of these strains is not known. Davies and colleagues showed, after sequencing 141 emm12 GAS isolates (58 scarlet fever and 83 non-scarlet-fever from mainland China and Hong Kong), that the absence of ssa is strongly associated with the absence of disease [15].

One could hypothesize that the acquisition by a determined genomic backbone of horizontally acquired genetic elements harboring a scarlet fever virulence factor is the key step for outbreaks. However, it is puzzling that several strains harboring these prophages have been shown to pre-exist the Hong Kong outbreak by at least 10 years [15]. Thus, even if the acquisition of these elements has probably resulted in a fitness gain for emm12 lineages over competing strains, this event alone cannot explain the outbreaks.

Several countries with well-established infectious disease National Surveillance Programs, such as Switzerland, show little interest in the surveillance of diseases caused by GAS, especially scarlet fever. Since several countries face a re-emergence of GAS-associated diseases; we believe that the burden of GAS diseases, including scarlet fever, needs to be carefully followed.

It appears clearly from both the mainland China/Hong Kong and the UK outbreak, that no single highly virulent GAS clone is uniquely responsible for these bursts. However, in Hong Kong a single emm12 clade was involved, the key microbiological event seemed to be the dissemination of genomic prophages/ICE harboring scarlet fever virulence determinants (ssa and speC particularly), conferring a new advantage to the recipient strains. But since these events predate the outbreaks, it also suggests that the combination of these microbiological events require changes in the hosts and/or environmental factors. In Great Britain, the prophage/ICE composition of strains circulating is uncertain.

One could suggest that the change in the national recommendations of GAS pharyngitis treatment in the UK (no more treatment) unlike what is proposed in the US, France, or Switzerland (6–10 days of antibiotics), may play an important role in the ongoing situation [20]. Further studies are needed and will hopefully answer this question. We thus believe that scarlet fever remains far from been fully understood and we probably still miss key host and environmental factors. These outbreaks emphasize the importance of epidemiologic surveillance coupled with microbiological studies, such as next generation sequencing studies, to detect changes in disease dynamics and in strains characteristics.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.